It is well documented that peripheral T cells from patients with metastatic cancer exhibit functional defects, including a diminished capacity to proliferate (Campoli, M., et al. Cancer Treat Res 123, 61-88 (2005); Gattinoni, L., et al. Nat Rev Immunol 6, 383-393 (2006); Rodriguez, P. C. & Ochoa, A. C. Immunol Rev 222, 180-191 (2008)). This loss of T cell function is likely a major factor in the failure of a host to mount an effective immune response to its own tumor. Tumor-reactive T cells are present in patients with cancer, but they are therapeutically ineffective as evidenced by tumor growth within these hosts (Hiraoka, N. Int J Clin Oncol 15, 544-551 (2010)). However, these same T cells recover functionally if they are removed from the suppressive tumor microenvironment, expanded to large numbers in vitro, and transferred back to the tumor-bearing hosts. This form of adoptive immunotherapy has been particularly effective leading to durable clinical responses in melanoma patients (Gattinoni, L., et al. Nat Rev Immunol 6, 383-393 (2006)). Thus, there is a need to restore function to dysfunctional tumor-reactive T cells in cancer immunotherapy research.
Antibodies that target certain T cell surface proteins have been shown to restore/enhance the function of tumor-reactive T cells in vivo in tumor-bearing hosts-anti-CTLA-4, anti-PD-1, anti-4-1BB, and anti-OX40 (Melero, I., et al. Nat Rev Cancer 7, 95-106 (2007); Fong, L. & Small, E. J. J Clin Oncol 26, 5275-5283 (2008); Peggs, K. S., et al. J Exp Med 206, 1717-1725 (2009); Curran, M. A., et al. Proc Natl Acad Sci USA 107, 4275-4280 (2010); Brahmer, J. R., et al. J Clin Oncol 28, 3167-3175 (2010)). These antibodies, alone or in combination, are being investigated as to whether they can restore T cell function in cancer patients. They could be more practical than adoptive T cell therapy because of their ease of administration and their potential value for patients with many different types of malignancies.
OX40 is a TNF-receptor family member that is expressed primarily on activated CD4+ and CD8+ T cells (Paterson, D. J., et al. Mol Immunol 24, 1281-1290 (1987); Mallett, S., et al. EMBO J 9, 1063-1068 (1990); Calderhead, D. M., et al. J Immunol 151, 5261-5271 (1993)). Preclinical cancer models have shown that OX40 agonists have potent anti-tumor activity against multiple tumor types, which is dependent on both CD4+ and CD8+ T cells (Kjaergaard, J., et al. Cancer Res 60, 5514-5521 (2000); Weinberg, A. D., et al. J Immunol 164, 2160-2169 (2000); Gough, M. J., et al. Cancer Res 68, 5206-5215 (2008); Piconese, S., Valzasina, B. & Colombo, M. P. J Exp Med 205, 825-839 (2008)). Immunization models have shown that OX40 agonists enhanced T cell proliferation, effector cytokine production, cytotoxicity, and decreased activation-induced cell death and increased the generation of memory T cells in non-human model systems (Gramaglia, I., et al. J Immunol 165, 3043-3050. (2000); Maxwell, J. R., et al. J Immunol 164, 107-112 (2000); Lee, S. W., et al. J Immunol 177, 4464-4472 (2006); Ruby, C. E. & Weinberg, A. D. Cancer Immunol Immunother 58, 1941-1947 (2009)). There remains a need to develop methods for stimulating the immune system of human cancer patients, and to determine whether the immune-enhancement treatment is effective.